HZI Community: Bereich Molekulare Biotechnologie (MBIO)http://hdl.handle.net/10033/6820
Bereich Molekulare Biotechnologie (MBIO)Fri, 09 Dec 2016 13:29:49 GMT2016-12-09T13:29:49ZTherapy of solid tumors using probiotic Symbioflor-2: restraints and potential.http://hdl.handle.net/10033/620605
Title: Therapy of solid tumors using probiotic Symbioflor-2: restraints and potential.
Authors: Kocijancic, Dino; Felgner, Sebastian; Frahm, Michael; Komoll, Ronja-Melinda; Iljazovic, Aida; Pawar, Vinay; Rohde, Manfred; Heise, Ulrike; Zimmermann, Kurt; Gunzer, Florian; Hammer, Juliane; Crull, Katja; Leschner, Sara; Weiss, Siegfried
Abstract: To date, virulent bacteria remain the basis of most bacteria mediated cancer therapies. For clinical application attenuation is required. However, this might result in a drastically lowered therapeutic capacity. Herein we argue that the E. coli probiotic Symbioflor-2, with a history of safe application may constitute a viable tumor therapeutic candidate. We demonstrate that Symbioflor-2 displays a highly specific tumor targeting ability as determined in murine CT26 and RenCa tumor models. The excellent specificity was ascribed to reduced levels of adverse colonization. A high safety standard was demonstrated in WT and Rag1-/- mice. Thus, Symbioflor-2 may represent an ideal tumor targeting delivery system for therapeutic molecules. Moreover, Symbioflor-2 was capable of inducing CT26 tumor clearance as result of an adjuvant effect on tumor specific CD8+ T cells analogous to the Salmonella variant SL7207. However, lower therapeutic efficacy against RenCa tumors suggested a generally reduced therapeutic potency for probiotics. Interestingly, concurrent depletion of Gr-1+ or Ly6G+ cells installed therapeutic efficacy equal to SL7207, thus highlighting the role of innate effector cells in restraining the anti-tumor effects of Symbioflor-2. Collectively, our findings argue for a strategy of safe strain application and a more sustainable use of bacteria as a delivery system for therapeutic molecules.Tue, 19 Apr 2016 00:00:00 GMThttp://hdl.handle.net/10033/6206052016-04-19T00:00:00ZCaveolin-1 influences human influenza A virus (H1N1) multiplication in cell culturehttp://hdl.handle.net/10033/620567
Title: Caveolin-1 influences human influenza A virus (H1N1) multiplication in cell culture
Authors: Sun, Lijing; Hemgård, Gun-Viol; Susanto, Sony A; Wirth, Manfred
Abstract: Abstract
Background
The threat of recurring influenza pandemics caused by new viral strains and the occurrence of escape mutants necessitate the search for potent therapeutic targets. The dependence of viruses on cellular factors provides a weak-spot in the viral multiplication strategy and a means to interfere with viral multiplication.
Results
Using a motif-based search strategy for antiviral targets we identified caveolin-1 (Cav-1) as a putative cellular interaction partner of human influenza A viruses, including the pandemic influenza A virus (H1N1) strains of swine origin circulating from spring 2009 on. The influence of Cav-1 on human influenza A/PR/8/34 (H1N1) virus replication was determined in inhibition and competition experiments. RNAi-mediated Cav-1 knock-down as well as transfection of a dominant-negative Cav-1 mutant results in a decrease in virus titre in infected Madin-Darby canine kidney cells (MDCK), a cell line commonly used in basic influenza research as well as in virus vaccine production. To understand the molecular basis of the phenomenon we focussed on the putative caveolin-1 binding domain (CBD) located in the lumenal, juxtamembranal portion of the M2 matrix protein which has been identified in the motif-based search. Pull-down assays and co-immunoprecipitation experiments showed that caveolin-1 binds to M2. The data suggest, that Cav-1 modulates influenza virus A replication presumably based on M2/Cav-1 interaction.
Conclusion
As Cav-1 is involved in the human influenza A virus life cycle, the multifunctional protein and its interaction with M2 protein of human influenza A viruses represent a promising starting point for the search for antiviral agents.Wed, 26 May 2010 00:00:00 GMThttp://hdl.handle.net/10033/6205672010-05-26T00:00:00ZIn Vivo Conditions Enable IFNAR-Independent Type I Interferon Production by Peritoneal CD11b+ Cells upon Thogoto Virus Infection.http://hdl.handle.net/10033/620545
Title: In Vivo Conditions Enable IFNAR-Independent Type I Interferon Production by Peritoneal CD11b+ Cells upon Thogoto Virus Infection.
Authors: Kochs, Georg; Anzaghe, Martina; Kronhart, Stefanie; Wagner, Valentina; Gogesch, Patricia; Scheu, Stefanie; Lienenklaus, Stefan; Waibler, Zoe
Abstract: Type I interferons (IFNs) crucially contribute to host survival upon viral infections. Robust expression of type I IFNs (IFN-α/β) and induction of an antiviral state critically depend on amplification of the IFN signal via the type I IFN receptor (IFNAR). A small amount of type I IFN produced early upon virus infection binds the IFNAR and activates a self-enhancing positive feedback loop, resulting in induction of large, protective amounts of IFN-α. Unexpectedly, we found robust, systemic IFN-α expression upon infection of IFNAR knockout mice with the orthomyxovirus Thogoto virus (THOV). The IFNAR-independent IFN-α production required in vivo conditions and was not achieved during in vitro infection. Using replication-incompetent THOV-derived virus-like particles, we demonstrate that IFNAR-independent type I IFN induction depends on viral polymerase activity but is largely independent of viral replication. To discover the cell type responsible for this effect, we used type I IFN reporter mice and identified CD11b(+) F4/80(+) myeloid cells within the peritoneal cavity of infected animals as the main source of IFNAR-independent type I IFN, corresponding to the particular tropism of THOV for this cell type.Sat, 15 Oct 2016 00:00:00 GMThttp://hdl.handle.net/10033/6205452016-10-15T00:00:00ZaroA-Deficient Salmonella enterica Serovar Typhimurium Is More Than a Metabolically Attenuated Mutant.http://hdl.handle.net/10033/620109
Title: aroA-Deficient Salmonella enterica Serovar Typhimurium Is More Than a Metabolically Attenuated Mutant.
Authors: Felgner, Sebastian; Frahm, Michael; Kocijancic, Dino; Rohde, M; Eckweiler, Denitsa; Bielecka, Agata; Bueno, Emilio; Cava, Felipe; Abraham, Wolf-Rainer; Curtiss, Roy; Häussler, Susanne; Erhardt, Marc; Weiss, Siegfried
Abstract: Recombinant attenuated Salmonella enterica serovar Typhimurium strains are believed to act as powerful live vaccine carriers that are able to elicit protection against various pathogens. Auxotrophic mutations, such as a deletion of aroA, are commonly introduced into such bacteria for attenuation without incapacitating immunostimulation. In this study, we describe the surprising finding that deletion of aroA dramatically increased the virulence of attenuated Salmonella in mouse models. Mutant bacteria lacking aroA elicited increased levels of the proinflammatory cytokine tumor necrosis factor alpha (TNF-α) after systemic application. A detailed genetic and phenotypic characterization in combination with transcriptomic and metabolic profiling demonstrated that ΔaroA mutants display pleiotropic alterations in cellular physiology and lipid and amino acid metabolism, as well as increased sensitivity to penicillin, complement, and phagocytic uptake. In concert with other immunomodulating mutations, deletion of aroA affected flagellin phase variation and gene expression of the virulence-associated genes arnT and ansB Finally, ΔaroA strains displayed significantly improved tumor therapeutic activity. These results highlight the importance of a functional shikimate pathway to control homeostatic bacterial physiology. They further highlight the great potential of ΔaroA-attenuated Salmonella for the development of vaccines and cancer therapies with important implications for host-pathogen interactions and translational medicine.Fri, 01 Jan 2016 00:00:00 GMThttp://hdl.handle.net/10033/6201092016-01-01T00:00:00Z